Bis-(alpha-hydroxy-alpha-arylaminoacetyl)-aryl-derivatives



United States Patent O "ice I 3,1163% Patented Dec. 31, 1963 in which X and Y are as defined above for Formula I. mg l pflxYiligiggAlvimgAcETYL) The condensation is carried out by treating the calcuooclift) -alated amount of a glyoxal of Formula III and an acid of Allin-DERIVATIVES Formula IV in the presence of a suitable solvent. The

Guide Cavallini and Elena Massarani, Milan, Italy, assignors to Francesco Vismara S.p.A.,. Casatencvo (Cor-no), Italy, a firm 5 solvent used is generally of the alcoholic or ether type, depending on the desired final products. In fact, reacting N0 Drawing Filed 18, 1961, 103,721 glyoxal hydrate in an organic reaction solvent which cgaims primity, appyicafion Italy 27, 1959 is not alcoholic and in particular is an inert solvent, such 6 Cl i (Cl, 250-471) as for example benzene, toluene, xylene, dioxane, cyclo- 10 hexane or other similar ones, the compounds of Formula This invention relates to novel bis-(a-hydroxy-a-aryl- I in which R represents hydrogen are obtained. Using inaminoacetyl)-aryl derivatives having antiviral activity, Stead an alcoholic solvent ROH, the compounds of Forparticularly against influenza virus (PR heptatitis virus mula I in which R represents a hydrocarbon radical, and (MHV Herpes simplex, Coxsackie virus, adenovires, precisely the residue of the alcohol used, are obtained. Cari-e virus, distemper virus, neutrotropic virus (CLM), 1 By condensing the glyoxal alcoholate the compounds of Newcastle disease virus, Echo virus and hemadsorption Formula I in which R represents a hydrocarbon radical virus. are obtained. In this case however it is advantageous to The compounds of this invention are represented by use an alcohol solvent corresponding to the alcoholate the following general formula: used. Thus for example if the alcoholate starting material FORMULA I YOOC Q- AnQ COOY -HNIICO o o O-(I3HNH X m OR X i hi h; is the glyoxal methylate it is preferred to run the reaction in the presence of methyl alcohol.

The condensation reaction is carried out at a temperature from about ambient or room temperature to the boiling point of the solvent used. The reaction time is from about 15 minutes to 24 hours depending on the temperatureand the chemical nature of the reagents, but preferably is from about minutes to eight hours at a temperature from about to 100 C.

The condensation products are usually isolated from A represents oxygen, sulfuns-ulfinyl, sulfionyl, methylene,

ethylene, a,fl-diethylethylene, vinylene, or. a,fi-diethylvinylene, and wherein n is an integer from 0 to 1; 30

R represents hydrogen or a hydrocarbon radical of from 1 to 12 carbon atoms, inclusive;

X represents hydrogen, hydro-xy, methoxy or acetoxy; and

Y represents hydrogen or lower alkyl of trom l to 4 carbon atoms, inclusive.

Ad-vantageous compounds of this invention are reprethe reaction mixture by cooling directly or first removing sented by the following general formula: the major portion of the solvent and then cooling, filtering FORMULA II YO o c IINII(FO o-n-0 O(|J H-NIL-QC o OY OR l 0R X in which; r the precipitate and recrystallizing from an appropriate 0 1 lane solvent. A j g i g g i ifgg f ggi ems/16m Vmy The glyoxal starting materials of Formula 111 are pre- R represents hydrogen, a lower saturated or unsaturated 5 55111 getfig k 31i21 :2:n f ig ggptiegog?2:23:35

al lat h d 0C: bon radical of from 1 to 8 car on I 7 Egg z l qcryclohexyl or benzyl- Friedel-Crafts acylation) or by treating corresponding di- X iqydrgen or hydroxyand halogen derivatives with an alkali metal alcoholate fol- Y renresents hydrogen methyl or ethyl, l wed by acid hydrolysis. More complete methods for n f the preparation of these starting materials are described rrcferred compounds of this invention are represented in copending Serial NO 41 765 filed y 11 1960 I y L. 1' E i a a byfomhla H f A Is slmlarly d6fined The following examples illustrate the compounds emhiyur-ogen or-lcmer alkyl of from 1 to 8 carbon braced by general Formula I and as exemplary are not particularly methyl or ethyl and X an are intended to limit the scope of the invention broadly dehydrogen.

The novel bis-(e-hydroxy-a-arylaminoacetyl)-aryl defined herein rivatives of Formula I are prepared by condensing the hydrate or alcoholate addition compound of a bis glyoxal A l i f 212 of 4 4z i h 1 1 1 1 Example 1 a g the following formula? drate in 50 cc. of anhydrous ethyl alcohol is heated at FORMULA III 69 C. and 3.3 g. of ethyl p-aminobenzoate is added. The

mixture is maintained at 60 C. for four hours with stirring and then part of the solvent is evaporated by distil- OHOOC CooHo lation. Cooling separates 4,4-bis-[a-ethoxy-a-(p-carbethin which A is as defined above for Formula I, with an yl y Y P l/ 56167 C- acid having the following formula:

FORMULA IV Example 2 COOY 70 To a solution of 2.72 g. of 4,4-biphenylylbisglyoxal hydrate in 50 cc. of dioxane heated to about 70 C. X is added 3 g. of p-aminobenzoic acid. The mixture is heated at reflux for five hours with stirring and then cooled and filtered to yield 4,4-bis-[ct-hydroxy-u-(p-carboxyphenyl am ino -acetyl] -biphenyl.

Operating under the same conditions and condensing 4,4'-biphenylylbisglyoxal hydrate with oand rn-aminobenzoic acid, yields respectively 4,4-bis[a-hydroxy-a- (o-carboxyphenylamino)-acetyl]-biphenyl and 4,4-bis- [a-hydroxy-a- (m-carboxyphenylamino -acetyl] -biphenyl.

Example 3 4,4-biphenylylbisglyoxal hydrate (2.72 g.) is dissolved at 60 C. in 50 cc. of anhydrous isopropyl alcohol and to this solution is added 3.3 g. of ethyl p-aminobenzoate. The mixture is maintained at 60 C. for five hours with stirring, then cooled and the precipitate separated by filtration to give 4,4-bis-[a-isopropoxy-u-(p-carbethoxyphenylamino)-acetyl]-biphenyl, MP. 164 C. (dec.).

Following the method described above and using instead benzyl alcohol yields 4,4'-bis-[a-benzyloxy-a- (p-carbethoxyphenylamino) -acetyl] -biphenyl.

Example 4 To 3.1 g. of 4,4-biphenylylbisglyoxal hydrate in 50 cc. of propargyl alcohol is added 3.3 g. of ethyl p-aminobenzoate. The mixture is heated at reflux for two hours, part of the solvent is then removed and the remainder cooled to give a precipitate of 4,4-bis-[a-propargyloxy-u- (p-carbethoxyphenylamino) -acetyl] -biphenyl.

Operating under the conditions described above and substituting the propargyl alcohol with allyl alcohol yields 4,4-bis [c allyloxy oc (p carbethoxyphenylamino)- acetyl] -biphenyl.

Example 6 3.2 g. of 4,4-bisglyoxalyldiphenylether hydrate is dissolved with heating in 60 cc. of anhydrous ethanol and to the solution is added 2.8 g. of p-aminobenzoic acid in 50 cc. of ethanol. The mixture is heated at 60 C. for four hours and then cooled to yield 4,4-bis-[a-ethoxy-a- (p carboxyphenylamino) acetyl] diphenylether, Ml. 261-262 C. (dec).

Example 7 6.4 g. of 4,4-bisglyoxalyldiphenylether hydrate is heated at 60 C. for two hours with 100 cc. of anhydrous dioxane. To the mixture is added 5.6 g. of p-aminobenzoic acid in 60 cc. of dioxane and heating is continued for another four hours. Cooling precipitates 4,4- bis-[a-hydroxy a-(p carboxyphenylamino) acetyl]-diphenylether, M.P. 259-260 C. (dec.).

Example 8 3.38 g. of 4,4'-bisglyoxalyldiphenylethane hydrate is dissolved with heating in 70 cc. of anhydrous ethanol and to the solution is added 2.8 g. of p-aminobenzoic acid in 50 cc. of ethanol. Following the procedure of Example 6 yields 4,4-bis-[a-ethoxy-a-(p-carboxyphenylamino)- acetyl]-diphenylethane.

Example 9 A solution of 3.35 g. of 4,4'-bisglyoxalyldiphenylsulfide hydrate in 100 cc. of anhydrous dioxane is treated with a solution of 2.8 g. of p-aminobenzoic acid in 50 cc. of dioxane following the procedure described in Example 7 to give 4,4-bis-[oz-hydroxy-a-(p-carboxyphenylamino)- acetyl] -diphenylsulfide.

Example 10 3.2 g. of 2.2-bisglyoxalyldiphenylether hydrate is dis solved with heating in anhydrous ethanol and to the solution is added 2.8 g. of methyl p-arninosalicylate. The mixture is heated at 60 C. for four hours and Worked up as in Example 6 to give 2,2-bis-[u-ethoxy-a-(3-hydroxy-4 carbomethoxyphenylamino)-acetyl] diphenylether.

Example 11 3.3 g. of 4,4-bisglyoxalylstilbene hydrate is dissolved with heating in 70 cc. of anhydrous methanol and to the solution is added 2.8 g. of p-aminobenzoic acid dissolved in 30 cc. of methanol. Heating is continued at 60 C. for another two hours. Working up as described in Example 6 yields 4,4-bis-[a-methoxy-a-(p-carboxyphenylamino)-acetyl]-stilbene.

Example 12 4.7 g. of 4,4'-bisglyoxalyldi henylsulfone hydnate is dissolved with heating in 70 cc. of methanol and to the solution is added 3.9 g. of p-aminoacetylsalicylic acid in 50 cc. of methanol. Heating is continued at 60 C. for five hours and then Worked up as described in Example 6 to give 4,4-bis-[a-methoxy-a-(3-acetoxy-4-carboxyphenylamino) -acetyl] -diphenylsulfone.

Example 13 A solution of 3.1 g. of 3,3'-bisglyoxalyldiphenylether hydrate in 70 cc. of dioxane is treated at 60 C. for four hours with 2.8 g. of p-aminobenzoic acid in 50 cc. of dioxane. Working up according to the method of Example 7 gives 3,3'-bis-[a-hydroxy-w-(p-carboxyphenylamino) -acetyl] -diphenylether.

Example 14 A solution of 7.7 g. of 2,2'-bisglyoxalyldiphenylsulfide hydrate in cc. of anhydrous ethanol is treated for three hours at 60 C. with a solution of 3.4 g. of 4- amin -2.-methoxybenzoic acid in 50 cc. of ethanol. Working up as described in Example 6 yields 2,2-bis-[a-ethoxy a (3-methoxy-4-carboxyphenylarnino)-acetyl]-diphenylsulfide.

Example I 5 3.2 g. of 4,4-bisglyoxalyldiphenylmethane hydrate dissolved with heating in 70 cc. of anhydrous ethanol is treated with 2.8 g. of p-aminobenzoic acid in 50 cc. of ethanol. Following the method described in Example 6 yields 4,4-biswethoxy-rx- (p-carboxyphenylamino) -acetyl] -diphenylmethane.

Example 16 3.6 g. of 4,4-bisglyoxa-lyldiphenylsulfoxide hydrate is heated at 60 C. for two hours with isopropyl alcohol. This solution is treated with 1.38 g. of anthranilic acid in 25 cc. of isopropyl alcohol and heating is continued for two hours. Cooling the solution yields 4,4-bis-[a-isopropoxy a (2-carboxyphenylamino)-acetyl]-diphenyl sulfoxide.

Similarly, employing n-butyl alcohol in the above reaction sequence gives the corresponding 4,4-bis-[a-butoxy- 06*(2-CflI'bOXYPhCl'lY1EiIIllI10) -acetyl] -diphenylsulfoxide.

Example 17 A solution of 4.0 g. of 4,4-bisglyoxalylfl-diethyldipheny lethane obtained by heating in 7 0 cc. of anhydrous ethanol is treated with 2.8 g. of p-anrinobenzoic acid in 50 cc. of ethanol. Following the procedure of Example 6 yields 4,4-bis-[a-epoxy-a-(p-carboxyphenylamino)-acetyl]-a,B-diethyl-diphenylethane.

Similarly, employing 3.9 g. of 4,4-bisglyoxalyl-a,fidiethylstilbene in the above reaction furnishes the correspending 4,4 bis-[a-ethoxy-a-(pearboxyphenylamino)- acetyl1-m,,l3-diethylstilbene.

Example 18 solution is added 3.6 g. of p-aminosalicylic acid. The mixture is heated at 60 C. for four hours and then cooled A mixture of 2.72 g. of 4,4-biphenylylbisglyoxal hyto yield 4,4'-bis-[u-ethoxy-oc-(3-hydroxy-4-carhoxyphenyldrate and 60 cc. of anhydrous n-octyl alcohol in 200 cc. amino)-arcetyl]-biphenyl. of anhydrous benzene is heated at reflux for 12 hours 5 Similarly, 4,4'-bisglyoxalyldiphenyletlior hydrate is reover a water trap (Org. Syn. 3, 382) having an inner funacted with :p-aminosalicyiic acid to give the corresponding nel charged With a mixture of phosphorus pentoxide and 4,4 bis-[aetl1oXy-a-(3hydroXy-4-earho: yphenylamino)- a. filter aid. Concentration of the mother liquor in vacuo acetyH-diphenylether. gives 4,4-biphenylylbisglyoxal nocty-late which is reacted What is claimed is:

in 150 cc. of benzene with 3 g. of p-aminooenzoic acid to 10 1. A chemical compound of the formula:

Yooo Q- FQ oooY HNHC|3O o C 0-? II-NH X OR OR X give 4,4'-bis-[a-(n ootyloxy)-ot-(p -carboxyphenylamino in which A is a member selected from the group consistacetylJ-biphenyl. ing of oxygen, sulfur, sulfinyl, sulrfonyl, methylene, ethyl- Similarly, following the above reaction sequence but one, ddiethyiethylene, vinylene and c,,8-dieth vinylene, employing g. of citronellol instead of the n-octyl alcoand wherein n is an integer from G to 1 bond; R is a hol yields the corresponding citronellylate which is reacted 20 member selected from the group consisting of hydrogen, with 3 g. of perninohenzoic acid to give 4,4'l)iS-[o:- aliphatic hydrocarbon of from 1 to 12 carbon atoms, citronellyloxy on (p carboxyphenylamino)-acetyl]-bicyclohexyl and benzyl; X is a member selected from the phenyl. group consisting of hydrogen, 'hydroxy, methoxy and Example 19 acetoxy; and Y is a member selected from the group consisting of hydrogen and lower alkyl of from 1 to 4 carbon Following the procedure of Example 1 but reacting 4 atoms, g. of butyl p-aminooenzoate with 2.72 g. of 4,4-oiphen- 2. A chemical compound of the formula:

Yooo nN r -rooo \OO-|HNH-COOY OR OR ylylbisglyoxal hydrate in anhydrous ethyl alcohol yields in which R is lower alkyl of from 1 to 8 carbon atoms 4,4 bis-[a-ethoXy-a- (p-carbobutoxyphenylamino)-ace-tand Y is lower alkyl of from 1 to 4 carbon atoms. yl]-biphenyl. 3. A chemical compound of the formula:

115020 o C{ HN-H(I:0 o -0 O(EH--NH -o 0 0 CzHs OCzHs OCzHs 4. A chemical compound of the formula: HO 0 o- HN-H(|JO o o O(|]H-NH 43 0 OH 00211 002m Example 20 5. 4,4 bis-[wethoxy-a-(p-carboxyp henyiamino)-acet- Following the procedure of Example 1 but reacting 45 ll l? I 2.72 g. of 4,4-biphenylylbisglyoxal hydrate in cc. of 4,4 Y- -(P* YP Y anhydrous ethyl alcohol with 3 g. of p-aminobenzoic acid fil p y 1d 4,4-b' tho carbon hen lamin'o -ace*- ir lib i th lf [a e W a (p 1p y L References Cited. in the file of this patent Example 21 5O Cavallini et al.: 1. Med. Pharm. Chem, 2, No. l, 99- 3.02 g. of 4,4'-bisglyoxalylbiphenyl hydrate is dissolved 106 in 50 cc. of anhydrous ethanol with heating and to the 

1. A CHEMICAL COMPOUND OF FORMULA: 